Type 2 diabetes has a devastating impact in the African American population. This grant proposal is the competitive renewal application for R01 DK663581 Genetics of African American Type 2 Diabetes. In the prior grant period extensive recruitment, genotyping, and analysis was carried out with the goal of identifying genetic loci which contribute to risk for type 2 diabetes (T2DM) in the African American population. Genetic risk factors for T2DM in African Americans appear largely different from those previously identified in European-derived populations. Thus, identification of T2DM loci in African Americans will not only provide insight into diabetes susceptibility in this high risk population, but will potentially identify novel pathways of diabetes risk. These studies have culminated in performance of the first Genome Wide Association Study (GWAS) of T2DM in African Americans. Specific aims of the study are to 1. Carry out a comprehensive analysis of the GWAS data; 2. Genotype high scoring SNPs from the GWAS in a two stage replication analysis consisting of a first stage of 1000 independent cases and 1000 controls, followed by further replication in a large collection of study samples containing T2DM and controls; 3. Perform a Meta-analysis of Wake Forest data with GWAS data from the Candidate Gene Association Resource (CARe) Project and the Family Investigation of Nephropathy in Diabetes (FIND) study resulting in a total of over 17,000 African American samples to confirm T2DM associations and identify genes contributing smaller effect sizes; and 4. Subject replicated loci to a combination of bioinformatic, molecular, and analytical approaches to comprehensively characterize variants/loci/genes which are associated with T2DM in African Americans. Successful completion of these aims will set the stage for future studies of mechanism of action of these loci at molecular, cellular, and organism levels to contribute to the long term goal of this work: to improve the prediction, prevention, and treatment of T2DM in African Americans. PUBLIC HEALTH RELEVANCE: This study is focused on identifying the gene which contributes to type 2 diabetes susceptibility in the African American population.